Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 4, Pages 1951-1961Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c12404
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Funding
- National Natural Science Foundation of China [22171238]
- Research Grants Council of Hong Kong [27301821]
- University of Hong Kong
- Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program
- Faculty of Science of the University of Hong Kong
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This study reports a reductive desymmetrization of halomalonic esters using dinuclear zinc catalysts. The resulting α-halo-β-hydroxyesters serve as important intermediates for the synthesis of drug analogs and polyhalogenated monoterpenes.
Enantioenriched tertiary alkyl halides are prevalent in bioactive molecules and can serve as versatile synthetic intermediates to construct complex structures. While conventional access to these motifs often hinges on stereoselective carbon-halogen or carbon-carbon bond formation reactions, desymmetric approaches using halogenated and prochiral tetrasubstituted carbons are largely elusive in comparison. Here, we report that a suite of dinuclear zinc catalysts with a prolinol- or pipecolinol-derived tetradentate ligand can reductively desymmetrize a large collection of easily available halomalonic esters to alpha-halo-beta-hydroxyesters. These polyfunctionalized tertiary alkyl fluorides, chlorides, and bromides proved to be useful intermediates toward fluorinated drug analogs and polyhalogenated monoterpenes. The facile intramolecular epoxidation of the chiral chloride and bromide products has also enabled expeditious access to natural products containing tertiary alcohol motifs.
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